The present invention is directed to a novel process for preparing arylpiperazinyl-ethyl (or butyl)-heterocyclic compounds and their pharmaceutically acceptable acid addition salts by reacting a piperazine salt with an alkyl halide.
U.S. Pat. No. 4,831,031 indicates that arylpiperazinyl-ethyl (or butyl)heterocyclic compounds may be prepared by reacting an N-arylpiperazine with a fused bicyclic compound. This coupling reaction is generally conducted in a polar solvent (such as a lower alcohol, dimethylformamide or methylisobutylketone) and in the presence of a weak base, and preferably the reaction is in the further presence of a catalytic amount of sodium iodide and a neutralizing agent for hydrochloride such as sodium carbonate.
Yevich et al., J. Med. Chem., 29, No. 3, pp. 359-369 (1986), relates to a method of producing 1-(1,2-benzisothiazol-3-yl)- and (1,2-benzisoxazol-3-yl)piperazine derivatives. Several reaction schemes are disclosed, including reaction schemes wherein coupling occurs in a free base.
Copending U.S. patent application Ser. No. 07/936,179 filed Aug. 26, 1992 (U.S. Pat. No. 5,206,366), relates to a process of preparing arylpiperazinyl-ethyl (or butyl)-heterocyclic compounds by reacting a monosubstituted piperazine with an alkyl halide.
Copending U.S. patent application Ser. No. 07/939,204 filed Sep. 1, 1992, relates to 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydr o-2H-indol-2-one hydrochloride monohydrate, and a process for preparing that compound comprising reacting anhydrous 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydr o-2H-indol-2-one with aqueous hydrochloric acid.
All of the documents and copending patent applications cited herein, including the foregoing, are hereby incorporated in this application in their entireties.
The present invention relates to a new and useful process for effecting coupling reactions of piperazine salt derivatives with alkyl halide derivatives that provide aryl piperazinyl-ethyl (or butyl)-heterocyclic compounds in greater yields than known methods. In the present invention, the coupling reaction is conducted in water. This aqueous based coupling process is not only more efficient but has a much lower environmental burden since the handling and disposal of organic solvents are eliminated. This process has not shown formation of byproducts and does not require special isolation procedures, e.g., extractions, distillations and recrystallizations. Also, the present invention results in a decrease in lumping during the coupling reaction.